1. Field of the Invention
The present invention involves the fields of immunology and medicine, and more particularly relates to immunization methods, and compositions used therewith, for immunizing young mammals, such as human infants and children, against at least one chronic immune mediated disorder, and, preferably, also against at least one infectious disease.
2. Related Background Art
Human Pediatric Immunization. A number of severe childhood diseases can strike early in life. Pertussis may pose a serious threat to infants under three months of age, and, during the heyday of the polio epidemic, paralytic cases were reported in the 6–12 month age group with disturbing frequency.
Consequently, to avoid any gap in immunity, it was thought desirable to initiate immunization before infants lost passive protection from maternal antibodies. However, the presence of maternal antibodies can modify or suppress the infants response to immunization, especially if the vaccine preparations are of low potency. The maturity of the infant's immune system is also a consideration, and premature immunization can result in immunological paralysis.
Accordingly, it has been generally recommended to postpone immunizations in developed countries where maternal antibodies provide protection against infant infectious diseases until after the age of 2 to 6 months, when the modifying effect of the maternal antibodies had disappeared. Therefore, immunizations should induce an active immune response before the infant loses this passive protection, so that there will be continuous protection from birth without any gap in immunity to natural diseases.
More recently, it has generally been recommended to begin infant immunizations, such as DTP (diphtheria, tetanus and pertussis) and OPV (oral polio virus), at younger ages, and many countries have carried out successful immunization studies and programs beginning at 6–8 weeks of age in developed countries (Expanded Programme on Immunization (1984); (1985)). Accordingly, current recommendations for infant immunization is to provide routine DTP and OPV immunization initiated at no earlier than 6 weeks of age in all developed countries.
The literature on immunization schedules for pediatric vaccines is voluminous, but the examples which follow indicate what has been tried.
Provenzano et al., New England J. Med., 273:959–965 (1965) gave a first dose of a plain pertussis vaccine at 6–24 hours after birth. In Group I, two more such doses were given at three week intervals, and then two doses of combined diphtheria, tetanus and pertussis vaccine (DTP) at one month intervals. In Group II, the initial plain pertussis immunization was followed by three DTP injections at one month intervals.
The authors reported that the immunization response in both groups was inadequate, and attributed it to immunological paralysis “induced by the vigorous immunization schedule employed and the initiation of immunization on the first day of life” In view of earlier studies, they recommended that immunization not be attempted under three weeks of age.
Dengrove, et al., Pediatric Res., 20:735 (1986) gave a first dose of DTP to infants before 4 days of age, and further doses at 2, 4 and 6 months of age. The immune responses to diphtheria and tetanus immunogens were acceptable, in contrast to their previous demonstration that “an early neonatal dose of DTP resulted in a lowered pertussis antibody response in the subgroup of infants who had low maternally acquired levels of antibody.”
Only 45 infants were treated, and therefore, even if this schedule could be effective to inhibit diabetes, it is unlikely that any of the infants actually were benefited (immune-mediated diabetes occurs in only one out of 200–300 individuals).
The immunization protocol used by Baraff, et al., Pediatrics, 73: 38–42 (1984) was similar, but the technology used to evaluate the immune response was more sophisticated. It was found that the IgG response to the pertussis lymphocytosis—promoting toxin (LPT) was lower and the IgM anti-FHA (filamentous hemagglutinin) response higher in the early immunization group than in controls. The authors were of the opinion that the anti-LPT response was of greater clinical significance and therefore concluded that neonatal immunization may be disadvantageous. This would have discouraged use of both Dengrovels and Baraff's protocols.
Perkins, et al., British Medical J., 68–71 (Jul. 12, 1958) investigated the response of infants to immunization with a killed poliomyelitis vaccine. The first dose was given to Group A at 1 week of age, Group B at six weeks of age, and Group C at ten weeks of age. A second dose was given four weeks later. Three different virus types were tested in these three groups.
Perkins et al. found that maternally transmitted antibodies interfered with the immune response of the infants to the vaccines. Maternal antibodies declined with age (the half life was about 21 days). The type 2 vaccine was the least susceptible to this interference, but according to table 4, it too, felt it (60% of Group C infants responded, as compared to 35% of those in Group A).
Based on these findings, Perkins et al. concluded “in order to avoid the inhibiting effect of the placentally transmitted antibody, immunization should at present be delayed until six to nine months after birth.”
Another study, by Spigland and Goldblum, Pediatrics 25:812–821 (1960) divided infants into groups A (1 and 2 months old), B (3 and 4 months old), and C (5 and 6 months old). Primary immunizations was either at (a) 0 and 21 days, or (b) 0, 7 and 21 days from the first immunization. The vaccine was the formalin-inactivated salk poliomyelitis vaccine. The authors concluded that “presence of maternal antibody seemed to interfere with active production of antibody,” and that “the greater the age of primary immunization, the better the response.”
In a recent pulse immunization study by John, British Medical Journal 289:88 (1984) the first dose of an oral poliomyelitis vaccine was given at 7, 14, 21, 28, 35 or 42 days of age, and the second and third doses at intervals of four weeks. The immune response to the oral vaccine, unlike the parenteral vaccine discussed previously, did not appear to be affected by the age of the infant. The authors recommended that children be immunized with the polio vaccine at 1 and 5 weeks, and with polio-plus-DPT at 9, 13, and 17 weeks. The present inventor believes that this immunization schedule would be disadvantageous as the late administration of pertussis would promote the development of diabetes and counteract any anti-diabetic effect of the early polio vaccine dosage.
Barrett, Jr., et al., J. Am. Med. Asso., 167:1103–6 (1958) considered whether it would be advantageous to combine the polio and DPT vaccines. The tetravalent vaccine was administered to children ranging in age from 2½months to 5 years. Only polio antigen response was measured. The study found that “older children respond much more dramatically than do the infants.”
Barrett, Jr. et al., Pediatrics, 30:720 (1962) gave a series of polio-DPT inoculations, beginning at various ages, and then at 1, 2, 3 and 4 months post-initial immunization. The first immunization was at (A) 1–2 days old, (B) 1–2 months old, (C) 3–4 months old or (D) 5–6 months old. Based on their observations, the authors recommended that the initiation of both polio and pertussis immunizations be withheld until the infants was three months of age.
A rather extensive review of the literature on DPT and oral poliomyelitis vaccine (OPV) immunizations has been given by Halsey and Galazky Bull. World Health Org., 63:1151–69 (1985). They compare the antibody response following one dose of OPV at 1–12 weeks of life (Table 1) with that to 2–3 doses beginning at 6–8 weeks of life (Table 2), and recommend that in countries where polio-myelitis has not been controlled, trivalent OPV be given at birth and at 6, 10 and 14 weeks of age. Pertussis vaccine schedules are reviewed in Table 3. The response to immunization beginning at 4 or more weeks was said to be almost as good as the results obtained by beginning at eight or more weeks. They recommended initiating DPT at six weeks of age.
Infants as young as 1–2 months old at the time of initial immunization have received a Hemophilus influenza (bacterial meningitis) (Hibtiter) vaccine (three doses at two month intervals.) Madore, et al., Pediatrics, 85:331–337 (1990). However, Madore, et al. stated that older children responded better than younger children, and their employer, Praxis Biologics, eventually recommended that its Hibtiter vaccine be given to children at 2 to 71 months of age (see PDR). Neonatal vaccination with Bacille Calmette-Guerin (BCG), and its impact on malignant disease, is briefly addressed by Grange and Stanford, Tubercle 71:61–64 (1990). A four dose vaccination schedule has been used to interrupt perinatal vertical transmission of hepatitis B virus, the first being given in the first week of life, and others at 1, 3 and 6 months of age.
While vaccines are subject to safety review, both before and after marketing approval, prior to the present invention, chronic immune mediated diseases, such as diabetes mellitus, were not considered vaccine complications. Many vaccines have been approved based on studies of only a few thousand recipients followed for only a short time after receiving the vaccine. These studies are inadequate to detect the effect of vaccines on chronic immune mediated diseases that are rare and don't develop until many years after a recipient received a vaccine. Current trials with new vaccines only compare results to people who received standard immunization. If both groups received vaccination starting at 2 months, which is now discovered to be associated with the increased risk then both groups will be associated with a higher than necessary risk of diabetes and other chronic immune mediated disorders. Additionally, current vaccine trials are not designed to look for complications of diabetes or other chronic immune mediated disorders which may not occur until 15 years, or more, after a person is immunized.
Likewise bioassays performed to show safety of vaccines are inadequate because the animals used are from strains that are not susceptible to vaccine induced chronic immune mediated diseases, such as diabetes.
The lack of concern over the ability of vaccines to induce a chronic immune mediated disorder (e.g., but not limited to, diabetes) is further evidenced by the lack of warnings on package inserts and labels of such products about such diseases.
As shown above, background art favors administration schedules that induce high levels of antibodies protective against the targeted infectious agent, and therefore typically require beginning immunization at a relatively late age (e.g., for DTP, at two months). The data presented in the present specification shows that such an immunization schedule can cause or at least substantially contribute to the development of chronic immune mediated disorders, e.g. diabetes, as discussed herein.
Animal Pediatric Immunization. Lee, U.S. Pat. No. 4,857,318 intra-peritoneally administered a vaccine against Bordetella pertussis to pigs when 7 and 21 days old, or 6 and 12 days old. Intra-peritoneal administration of vaccines to humans is usually undesirable because of the risk of perforating the intestine. Green, U.S. Pat. No. 4,625,015 administered an influenza immunogen to mice at 28, 42 and 56 days after birth. The immunogen was adjuvanted with Freund's complete adjuvant, which is too toxic for human use. In vaccinating humans against influenza, FCA would have to be omitted, with a consequent reduction in the overall immunizing effect. Green does not explain how to adapt his agent or protocol for immunizing humans.
Kuzehara, U.S. Pat. No. 5,151,023 administered a single dose of a combined Hepatitis A and B vaccine to guinea pigs and mice, subcutaneously, at 28 days of age.
Chronic Immune Mediated Disorders. Many chronic immune mediated disorders, such as immune mediated cancers and hyperactive immune responses, can be induced or inhibited by cells of the immune system. Environmental stimuli can affect whether those genetically predisposed to a chronic immune mediated disorder will develop symptoms or not. For example, it is not uncommon for one identical twin to have a chronic immune mediated disorder (e.g., type I diabetes mellitus) and the other identical twin to be free of the disorder.
Several methods have been used to modulate an immune response in order to treat autoimmunity or early stages of diabetes mellitus (e.g., as disclosed in U.S. Pat. No. 4,710,380).
Immunosuppressive agents, including both general immuno-suppressants and antigen specific tolerizing agents, have been used to some extent to inhibit or treat chronic immune mediated disorders like autoimmunity. General immunosuppressants can lead to overwhelming infections and other toxicities as in bone destruction associated with corticosteroids and kidney disease associated with cyclosporine.
Antigen-specific agents that cross-react to a specific autoantigen have been employed to down-regulate immune responses to a particular autoantigen. An example of this approach is contained in PCT patent application (PCT/US90/01397, WO/10449) which discloses the use of antigens which cross-react with a 65 Kd heat shock protein as tolerizing agents. Alternatively, PCT/US91/00240 (WO 92/00755) discloses utilizing sub-immunogenic amounts of an antigen which cross-reacts to alloimmune serum, in order to tolerize individuals. The problem with antigen specific agents is that one often does not know all the autoantigens involved in an autoimmune disease and the mechanism requires knowledge of such molecules.
Effect of Immunogens on Immune Disorders. Harada, et al. (1990) reported that a single intravenous injection of live BCG into 5 or 10 week old NOD mice suppressed insulitis and overt diabetes, while an injection into 15 week old mice was somewhat less suppressive.
The dose given by Harada, 0.25–1 mg, is, on a per kg body weight basis (about 8–32 mg/kg) equivalent to a human dose which would not be considered pharmaceutically acceptable. It is not unclear whether Harada's findings regarding the effects of immunication with a live organism are extrapolatable to immunization with inactivated organisms or purified antigens as a live organism which provides continuing exposure of the host to the organism's antigens. BCG's effect may be attributable to its heat shock protein, a known tolerogen, rather than to a specific immunogenic effect. BCG vaccination has also been inconclusively reported to be associated epidemiologically with both an increased (Salonen, 1975) and decreased (Hems, 1971) incidence of childhood leukemia (Grange, 1990).
Huang, et al (1984) administered one dose of a whole cell Bordetella pertussis vaccine to mice which were at least 45 days old. The dose was given from 10 days before to 30 days after injection of streptozotocin (STZ), which produces a form of insulin-dependent diabetes. The pertussis vaccine aborted the development of IDD as a result of a single injection of STZ. Kolb, et al (1987) also looked at the effects of a pertussis vaccine in a streptozotocin-induced diabetes mouse model. The streptozotocin was administered when the mice were 8–11 weeks of age. The vaccine was given at day −3, +8, or +14 relative to STZ initiation. Given at day −3, it partially suppressed the hyperglycemia, while when given at days −8 and −14, it strongly enhanced it.
As admitted by Huang et al. (1991), “results from streptozotocin-induced IDDM experiments are difficult to extrapolate to type I IDDM because the correlation between chemically-induced diabetes and a “natural” development of autoimmune diabetes is unclear.” Consequently, Huang et al (1991) examined the anti-diabetic effect of pertussigen in the genetically predisposed NOD mouse. These mice were give four injections of pertussigen at four week intervals, starting when the mice were 2 (Group 1) or 4 (Group 2 and 3) weeks of age. According to the authors, “although the time at which IDDM was first observed was delayed by several weeks, the incidence rates were not significantly different from those of untreated control NOD mice.”
Toyota et al (1978) administered the islet activating protein of Bordetella pertussis to spontaneously diabetic rats aving a weight of 300–400 g. While the age of the rats is not stated, this body weight could not be attributed to a rat younger than 42 days. Furthermore, the animals were already diabetic before the administration of the protein thus the administration was intended as a therapy as opposed to a method of immunization.
It has recently been suggested that vaccination against measles may influence a reduction in the incidence of diabetes, however the data obtained was inconclusive because it failed to look at those who did not receive the vaccine and who did not develop the disease (Blom, 1991). These individuals are here discovered to in fact be at lower risk for developing diabetes than those who received the vaccine.
Effects of Immunomodulators on Immune Disorders. Several papers discuss the effect of OK-432, a streptococcal preparation, on diabetes in mice. (Toyota, et al. 1986; Shintani, et al. 1990). Toyota et al., 1986, gave two clinical units of OK-432 to mice every week from 4–24 weeks of age. Shintani, et al. (1990) also tested schedules of weekly immunization at 4–15, 4–9, and 10–15 weeks of age. Weekly injections were needed at a dose of approximately 0.1 mg/20 g, (5 mg/kg or 100 KE/kg) mouse to provide the protective effect (Shintani, Satoh, Seino, et al 1990), while pharmaceutically acceptable clinical doses would be 0.07 KE/kg or 1400 times less.
OK-432 is a pyretic agent. See Shinoda, et al. Acta Urologica Japonica, 38:1299–13ct (1992); Luh et al., Cancer, 69:674–9 (1992), Imamura, et al., Cancer, 68:259–63 (1991); Ogita, et al., J. Pediatric Surgery, 26:263–8 (1991). While it may be reasonable to prescribe it to a patient with cancer, it would not be clinically indicated for prevention of diabetes in youngsters. Young children are particularly prone to seizures as a result of high fevers. Ogita et al. used OK-432 only to treat surgically unresectable lymphangiomas in children.
Oldstone (1988) inoculated NOD mice with live, unattenuated, lymphocytic choriomeningitis virus (LCMV) either intracerebrally at birth with LCMV ARM536 or intravenously with “clone 13” at six weeks of age. Both treatments prevented the spontaneous development of type 1 diabetes characteristic of NOD mice. This work was elaborated upon by Oldstone, et al. (1990), who inoculated NOD mice intracerebrally, within the first eighteen hours of life, with various LCMV strains and reassortants. Schwimmbeck, et al. (1989) found that acute infection with LCMV at 30 days of age abrogated diabetes in BB rats.
However, these inoculations did not immunize the rodents against LCMV, and therefore did not offer protection against an infectious disease. Indeed, the administration infected the rodents with the virus, which persisted throughout the animal's lifespan, and altered the cytotoxicity of the host's T lymphocytes. The present invention does not contemplate inoculating a subject with a live, unattenuated virus. Lympho-tropic viruses are potentially very dangerous, as the case of HIV illustrates, and it would be difficult to win clinical acceptance of such a virus as a human therapeutic agent. Moreover; intra cerebral administration of vaccines to humans is undesirable because of the risks of damaging brain cells or inducing meningitis. In any event, the administration of other viruses has been shown to increase the incidence of diabetes (Guberski et al, 1991: Kilham's rat virus in BB/Wor rats).
Several other agents have to be used in attempts to alter the development of immune mediated disorders. Specific lympho-kines like IL-2 (e.g., according to Serreze et al, 1989) and tumor necrosis factor (e.g., according to Satoh et al, 1989) have also been employed to attempt to treat or prevent immune mediated disorders thought to be caused by lymphokine defects, by using multiple injections. However, purified lymphokines are relatively toxic, and expensive, and have short half lives.
Freund's adjuvant (Sadelain et al, 1990) has also been used to delay the development of diabetes in NOD mice. However, this adjuvant is not suitable for vaccine use in mammals at levels comparable to those used by Sadelein et al, (1990) due to its toxic effects. Freund's adjuvant can cause plasmacytomas as well as granulomas.
The use of anti-receptor and immune modulating agents (such as products that can block specific receptors, activate specific receptors, or cause the release of suppressor factors) generally requires repeated injections at high doses, e.g., in the mg/kg of body weight range. Examples of anti-receptor immunogens include monoclonal antibodies (e.g., U.S. Pat. No. 4,695,459) and lectins like Concanavalin A (e.g., Pearce and Peterson, 1991). Pharmaceutical use of monoclonal antibodies reactive to the antigen specific T-cell receptor have been shown to be associated with an increase in human lymphoid tumors and thus anti-receptor ligands reactive to the this T-cell receptor are unlikely to be pharmaceutically acceptable.
In conclusion, it has heretofore not been clearly shown or recognized that pharmaceutically acceptable doses of pharmaceutically acceptable immunogens can prevent chronic immune mediated disorders. The related art has also not demonstrated whether such agents would be of value in preventing chronic immune mediated disorders in mammals, especially humans, that are immunized early in life. The related art has also not shown when or how to administer such agents to a mammal which being immunized early in life against infectious diseases, in order to prevent or reduce the prevalence/incidence/frequency/severity of chronic immune mediated disorders.
Citation of documents herein is not intended as an admission that any of the documents cited herein is pertinent prior art, or an admission that the cited documents is considered material to the patentability of any of the claims of the present application. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.